Interplay between the Endocrine and Innate Systems of Drosphila

果蝇内分泌系统和先天系统之间的相互作用

• 批准号: 10406987
• 负责人: Eric H Baehrecke
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406987
• 关键词: Adrenal Cortex Hormones; Affect; Animals; Anti-Bacterial Agents; Antiinflammatory Effect; Architecture; Autoimmune Diseases; Automobile Driving; Autophagocytosis; Bacterial Infections; Binding Sites; Biological; Biological Assay; Biological Models; CRISPR/Cas technology; Cell Death; Chemicals; Chromatin; Communicable Diseases; Cues; Culicidae; Data; Dehydration; Desiccation; Development; Drosophila genus; Drosophila melanogaster; Ecdysone; Ecdysterone; Elements; Endocrine; Endocrine system; Eukaryota; Eye; Genes; Genetic; Genetic Screening; Genetic Transcription; Glucocorticoids; Gonadal Steroid Hormones; Grant; Hormonal; Host Defense; Human; Immune; Immune response; Immune signaling; Immunity; Immunosuppression; Infection; Inflammatory Response; Innate Immune Response; Innate Immune System; Insect Vectors; Insecta; Kidney; Knowledge; Malaria; Malpighian Tubules; Mammals; Mediating; Metabolism; Methods; Microbe; Modality; Modeling; Molecular; Molecular Probes; Morbidity - disease rate; Mutate; Natural Immunity; Organism; Output; Pathway interactions; Physiological; Play; Production; Publishing; Pupa; Regulation; Reproduction; Research; Role; Salivary Glands; Signal Pathway; Signal Transduction; Steroids; Stress; Study models; System; Therapeutic; Time; Tissues; Translating; Vector-transmitted infectious disease; Vitamin D; West Nile virus; Zika Virus; adaptive immune response; antimicrobial peptide; assault; biological adaptation to stress; cytokine; defense response; design; experimental study; fly; hormonal signals; improved; in vivo; innate immune pathways; microbial; mortality; novel; receptor; response; steroid hormone; tool; transcription factor; vector transmission

Project Summary/Abstract Innate immunity is an ancient defense response that evolved with the earliest metazoan creatures, and is the first line of defense against microbial infection. These responses rely on the recognition of microbes by germline-encoded receptors, and drive the production of numerous chemical, biological, and cellular defense responses. In the face of constant microbial assault, innate immunity is essential for the survival of nearly all multicellular organisms. On the other hand, over-exuberant or inappropriate innate immune responses are the underlying cause of morbidity and mortality associated with many infectious and autoimmune diseases. The endocrine system, through steroids as well as sex hormones and vitamin D, has profound pro- or anti- inflammatory effects on the innate immune response. This crosstalk between the innate immune and endocrine systems is found throughout the animal kingdom, and likely evolved with some of the earliest animals. This proposal uses the fruit fly Drosophila melanogaster as a model for the study of these interactions. Flies offer many advantages for these studies, including experimental tractability with arguably the most robust genetic system for in vivo studies, extensive knowledge of steroid hormone regulatory networks, and an innate immune system without the complexity of the adaptive immune response. Furthermore, many aspects of the innate immune responses are highly conserved with mammals, and discoveries made in flies can be translated into paradigm shifting findings in mammals. Particularly relevant for this proposal are the conserved NF-κB signaling pathways, which drive the immediate response to infection, and the modulation of these signaling pathways by steroid hormones. A thorough mechanistic analysis of how the innate immune response is regulated by steroid hormones in the Drosophila model system will provide a deeper understanding of these ancient regulatory interactions, and are likely to identify new avenues for manipulating these interactions in vector insects and/or mammals. Preliminary data demonstrate that the insect steroid hormone 20-hydroxyecdysone has a profound enhancing effect on NF-κB dependent innate immune responses, through regulating the expression of the bacterial sensing receptor PGRP-LC. This regulatory network enables the ecdysone to prime the innate immune response, creating more effective immune defenses in times of stress. The experiments outlined in Aim 1 are designed to elucidate the molecular mechanisms underlying this hormonal control of immunity, while Aim 2 will probe the molecular and cellular mechanisms by which the steroid ecdysone responds to stress and primes immune defenses. In Aim 3, we will probe the role steroid-regulated immune signaling in driving developmentally programmed autophagic cell death and tissue degradation. All three of these Aims build upon, and extend in exciting new directions, the findings from our previous cycle of support for this grant.

项目总结/摘要 先天免疫是一种古老的防御反应，与最早的后生动物一起进化， 是抵御微生物感染的第一道防线这些反应依赖于微生物的识别， 生殖细胞编码的受体，并驱动许多化学，生物和细胞防御的产生 应答面对不断的微生物攻击，先天免疫对几乎所有生物的生存至关重要。 多细胞生物另一方面，过度旺盛或不适当的先天免疫反应是免疫缺陷的主要原因。 与许多感染性和自身免疫性疾病相关的发病率和死亡率的根本原因。的 内分泌系统，通过类固醇以及性激素和维生素D，有深刻的亲或抗- 炎症对先天免疫反应的影响。先天免疫和内分泌之间的相互作用 系统在整个动物界都有发现，并且可能与一些最早的动物一起进化。这 该提案使用果蝇Drosophila melanogaster作为研究这些相互作用的模型。苍蝇提供 这些研究的许多优点，包括实验的易处理性，可以说是最强大的遗传学， 用于体内研究的系统，类固醇激素调节网络的广泛知识，以及先天免疫 系统没有适应性免疫反应的复杂性。此外，许多方面的先天 免疫反应在哺乳动物中是高度保守的，在苍蝇中的发现可以转化为 在哺乳动物中的范式转变发现。与此建议特别相关的是保守的NF-κB 信号通路，驱动对感染的即时反应，以及这些信号的调节 通过类固醇激素的途径。 一个彻底的机制分析如何先天免疫反应是由类固醇激素调节， 果蝇模型系统将提供对这些古老的调节相互作用的更深入的理解， 有可能确定在媒介昆虫和/或哺乳动物中操纵这些相互作用的新途径。 初步数据表明，昆虫类固醇激素20-羟基蜕皮激素具有深刻的增强作用， 通过调节细菌的表达，对NF-κB依赖性先天免疫应答的影响 敏感受体PGRP-LC。这种调节网络使蜕皮激素能够启动先天免疫系统， 反应，在压力下创造更有效的免疫防御。目标1中概述的实验是 旨在阐明这种激素控制免疫的分子机制，而Aim 2将 探索类固醇蜕皮激素对压力和刺激反应的分子和细胞机制 免疫防御在目标3中，我们将探讨类固醇调节的免疫信号传导在驾驶中的作用。 发育程序性自噬细胞死亡和组织降解。所有这三个目标都建立在， 并在令人兴奋的新方向上扩展我们上一轮资助的发现。